Genomic and Functional Studies of Dysplasia-Associated Arterial Diseases
发育不良相关动脉疾病的基因组和功能研究
基本信息
- 批准号:10349917
- 负责人:
- 金额:$ 92.11万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-02-01 至 2029-01-31
- 项目状态:未结题
- 来源:
- 关键词:AllelesAneurysmArterial DisorderBedsBiologicalBiological FactorsBiological ModelsBlood VesselsCardiovascular ManifestationCardiovascular systemCell modelCessation of lifeClinicalComplexComputer AnalysisDiseaseDissectionDysplasiaExtracellular MatrixFibromuscular DysplasiaGenesGeneticGenetic Predisposition to DiseaseGenomicsGoalsGrowthHeritabilityHeterogeneityHypertensionLaboratoriesMedialModelingMolecularMolecular GeneticsMorbidity - disease rateMyocardial InfarctionOutcomePathologicPhenotypePopulationPrecision HealthPredispositionPreventionResolutionResourcesRoleSex DifferencesSmooth MuscleStenosisStrokeSusceptibility GeneTestingVariantVascular DiseasesVascular Smooth MuscleWomanarterial remodelingbiobankbiological sexclinical diagnosisdisease diagnosisexperimental studygenetic approachgenetic architecturegenetic variantin vitro Modelin vivoinsightmortalitymouse modelnovel diagnosticsnovel therapeutic interventionvariant of unknown significance
项目摘要
Project summary
Fibromuscular dysplasia (FMD) is a non-atherosclerotic, systemic arteriopathy with excess burden on women.
FMD may have varying manifestations, including hypertension, stroke and myocardial infarction, among
others, depending on the arterial beds involved by arterial stenosis, aneurysm, dissection or tortuosity. Thus,
the clinical diagnosis of FMD encompasses a spectrum of arterial dysplasia phenotypes, and these may be
either sporadic or familial. Arterial medial fibrodysplasia underlies the pathologic arterial remodeling and
susceptibility to loss of arterial integrity, and genetic susceptibility loci identified thus far implicate arterial
smooth muscle and its corresponding extracellular matrix. The genetic architecture of these dysplasia-
associated arterial diseases is emerging as variable, with contributions of complex genetic architecture, rare
heritable variants in a subset of cases, and potential modifier genes. The proposed studies will
comprehensively characterize the genetic and allelic spectrum, and test the hypothesis that the molecular and
functional basis of these genetic influences, while operative in a model of locus and allelic heterogeneity,
converge upon alterations of the vascular smooth muscle matricellular unit. The goal of this R35 proposal is to
precisely define the genetic basis of arterial fibrodysplasia and employ relevant model systems for gene and
variant mechanistic testing, resolution of genetic variants of uncertain significance, testing influences of
potential modifier genes, and analysis of regulatory mechanisms, particularly those relevant to vascular sex
differences. This proposal builds upon strengths in vascular disease characterization, high-throughput genetic
and genomic applications, computational analysis, and molecular genetic approaches in model systems. We
will conduct high throughput targeted gene sequencing to define the allelic spectrum of the involved genes in
our clinical and biorepository resources, followed by hypothesis driven experiments in vascular cell and murine
models for in vitro and in vivo definition of the mechanisms of the genetic findings impacting the matricellular
components which are altered in arterial fibrodysplasia. The role of biologic sex and factors underlying relevant
sex differences in arterial remodeling will be determined across the experiments. The outcome of this R35 and
the proposed studies will be the successful integration of genomics and functional studies to provide new
insights into the mechanisms of arterial dysplasia. The completion of these studies will provide critical and
urgently needed biologic insights that will advance precision health objectives including disease diagnosis,
prevention, and treatment, and to reduce the burden of cardiovascular morbidity and mortality.
项目总结
纤维肌肉发育不良(FMD)是一种女性负担过重的非动脉粥样硬化性全身性动脉疾病。
口蹄疫可能有不同的表现,包括高血压、中风和心肌梗死
其他的,取决于动脉狭窄、动脉瘤、夹层或曲折所涉及的动脉床。因此,
FMD的临床诊断包括一系列动脉发育不良表型,这些表型可能是
要么是零星的,要么是家族的。动脉中膜纤维异常增殖症是病理性动脉重构和
动脉完整性丧失的易感性和迄今发现的遗传易感基因座与动脉
平滑肌及其相应的细胞外基质。这些异型增生的遗传结构-
相关的动脉疾病是作为变量出现的,与复杂的遗传结构有关,罕见
部分病例中的可遗传变异,以及潜在的修饰基因。拟议的研究将
综合表征遗传和等位基因谱,并检验分子和等位基因谱的假设
这些遗传影响的功能基础,虽然在基因座和等位基因异质性模型中起作用,
在血管平滑肌基质细胞单位改变时汇聚。此R35提案的目标是
准确定义动脉纤维发育不良的遗传基础,并使用相关的基因和模型系统
变种机械测试,不确定意义的遗传变种的解析,测试的影响
潜在修饰基因,以及调节机制的分析,特别是与维管性有关的那些
不同之处。这一建议建立在血管疾病表征、高通量基因
以及模型系统中的基因组应用、计算分析和分子遗传学方法。我们
将进行高通量有针对性的基因测序,以确定涉及的基因的等位基因谱
我们的临床和生物信息库资源,随后是血管细胞和小鼠的假设驱动实验
影响基质细胞的遗传发现机制的体外和体内模型
动脉纤维异常增殖症中改变的成分。生物性别的作用及相关因素
动脉重塑的性别差异将通过实验来确定。这个R35的结果和
建议的研究将为基因组学与功能研究的成功结合提供新的
对动脉发育不良机制的洞察。这些研究的完成将提供关键和
迫切需要的生物学见解将促进包括疾病诊断在内的精确健康目标,
预防和治疗,并减少心血管疾病发病率和死亡率的负担。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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SANTHI K GANESH其他文献
SANTHI K GANESH的其他文献
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{{ truncateString('SANTHI K GANESH', 18)}}的其他基金
Genomic and Functional Studies of Dysplasia-Associated Arterial Diseases
发育不良相关动脉疾病的基因组和功能研究
- 批准号:
10551914 - 财政年份:2022
- 资助金额:
$ 92.11万 - 项目类别:
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